Photoredox Catalysis in a Complex Pharmaceutical Setting: Toward the Preparation of JAK2 Inhibitor LY2784544

We report a detailed investigation into the application of visible light-mediated photocatalysis to a challenging bond construction in a complex pharmaceutical target. The optimized reaction allowed the direct coupling of <i>N</i>-methylmorpholine with an unfunctionalized pyridazine in good yield and selectivity, and with high purity of the product isolated via crystallization. The reaction also facilitated the expedient synthesis of a range of analogues via the use of other commercially available <i>N</i>-methyl substituted tertiary amines, and therefore it represents an attractive tool for medicinal chemistry. Furthermore, a number of other interesting photoredox reactions were discovered during the course of this investigation, such as a formal methylation reaction via C–N bond cleavage, functionalization of C–H bonds alpha to amides, and a visible light-mediated iminium ion reduction

A Photochemical Strategy for Lignin Degradation at Room Temperature

The development of a room-temperature lignin degradation strategy consisting of a chemoselective benzylic oxidation with a recyclable oxidant ([4-AcNH-TEMPO]­BF₄) and a catalytic reductive C–O bond cleavage utilizing the photocatalyst [Ir­(ppy)₂(dtbbpy)]­PF₆ is described. This system was tested on relevant lignin model substrates containing β-O-4 linkages to generate fragmentation products in good to excellent yields

Friedel–Crafts Amidoalkylation via Thermolysis and Oxidative Photocatalysis

Friedel–Crafts amidoalkylation was achieved by oxidation of dialkylamides using persulfate (S₂O₈^2–) in the presence of the visible light catalyst, Ru­(bpy)₃Cl₂, at room temperature, via a reactive <i>N</i>-acyliminium intermediate. Alternatively, mild heating of the dialkylamides and persulfate afforded a metal and Lewis acid-free Friedel–Crafts amidoalkylation. Alcohols and electron-rich arenes served as effective nucleophiles, forming new C–O or C–C bonds. In general, photocatalysis provided higher yields and better selectivities

Light-Mediated Reductive Debromination of Unactivated Alkyl and Aryl Bromides

Cleavage of carbon–halogen bonds via either single-electron reduction or atom transfer is a powerful transformation in the construction of complex molecules. In particular, mild, selective hydrodehalogenations provide an excellent follow-up to the application of halogen atoms as directing groups or the utilization of atom transfer radical addition (ATRA) chemistry for the production of hydrocarbons. Here we combine the mechanistic properties of photoredox catalysis and silane-mediated atom transfer chemistry to accomplish the hydrodebromination of carbon–bromide bonds. The resulting method is performed under visible light irradiation in an open vessel and is capable of the efficient reduction of a variety of unactivated alkyl and aryl substrates

Functionally Diverse Nucleophilic Trapping of Iminium Intermediates Generated Utilizing Visible Light

Our previous studies into visible-light-mediated aza-Henry reactions demonstrated that molecular oxygen played a vital role in catalyst turnover as well as the production of base to facilitate the nucleophilic addition of nitroalkanes. Herein, improved conditions for the generation of iminium ions from tetrahydroisoquinolines that allow for versatile nucleophilic trapping are reported. The new conditions provide access to a diverse range of functionality under mild, anaerobic reaction conditions as well as mechanistic insights into the photoredox cycle

Visible Light-Mediated Atom Transfer Radical Addition via Oxidative and Reductive Quenching of Photocatalysts

Herein, the development of visible light-mediated atom transfer radical addition (ATRA) of haloalkanes onto alkenes and alkynes using the reductive and oxidative quenching of [Ir­{dF­(CF₃)­ppy}₂(dtbbpy)]­PF₆ and [Ru­(bpy)₃]­Cl₂ is presented. Initial investigations indicated that the oxidative quenching of photocatalysts could effectively be utilized for ATRA, and since that report, the protocol has been expanded by broadening the scope of the reaction in terms of the photocatalysts, substrates, and solvents. In addition, further modifications of the reaction conditions allowed for the efficient ATRA of perfluoroalkyl iodides onto alkenes and alkynes utilizing the reductive quenching cycle of [Ru­(bpy)₃]­Cl₂ with sodium ascorbate as the sacrificial electron donor. These results signify the complementary nature of the oxidative and reductive quenching pathways of photocatalysts and the ability to predictably direct reaction outcome through modification of the reaction conditions

Tandem Dienone Photorearrangement–Cycloaddition for the Rapid Generation of Molecular Complexity

A tandem dienone photorearrangement–cycloaddition (DPC) reaction of novel cyclohexadienone substrates tethered with various 2π and 4π reaction partners resulted in the formation of polycyclic, bridged frameworks. In particular, use of alkynyl ether-tethered substrates led to (3 + 2) cycloaddition to afford strained alkenes which could be further elaborated by intra- and intermolecular cycloaddition chemistry to produce complex, polycyclic chemotypes

Preparative Scale Demonstration and Mechanistic Investigation of a Visible Light-Mediated Radical Smiles Rearrangement

A visible light-mediated Smiles rearrangement providing the difluoroethanol motif has been shown to reliably operate on preparative scale up to 100 g of starting material. Mechanistic investigation has revealed the reaction proceeds predominantly via a radical chain process that in some instances can be initiated via visible light or thermal activation in the absence of a photocatalyst. The reaction was demonstrated in continuous flow, with visible light and thermal initiation using a thiophene substrate relevant to pharmaceutical development

Tandem Dienone Photorearrangement–Cycloaddition for the Rapid Generation of Molecular Complexity

A tandem dienone photorearrangement–cycloaddition (DPC) reaction of novel cyclohexadienone substrates tethered with various 2π and 4π reaction partners resulted in the formation of polycyclic, bridged frameworks. In particular, use of alkynyl ether-tethered substrates led to (3 + 2) cycloaddition to afford strained alkenes which could be further elaborated by intra- and intermolecular cycloaddition chemistry to produce complex, polycyclic chemotypes

Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles

A net redox-neutral method for the decarboxylative alkylation of heteroarenes using photoredox catalysis is reported. Additionally, this method features the use of simple, commercially available carboxylic acid derivatives as alkylating agents, enabling the facile alkylation of a variety of biologically relevant heterocyclic scaffolds under mild conditions